This invention relates to the use of cyclopenta[g]quinazoline derivatives. More particularly it relates to cyclopenta[g]quinazoline derivatives for the treatment of rheumatoid arthritis (RA) and acute myeloid leukaemia (AML).
Cyclopenta[g]quinazoline derivatives showing a good level of activity both as regards their ability to inhibit thymidylate synthase (TS) and also as regards their anticancer activity against various cell lines have been developed.
WO 94/11354 A1 (British Technology Group Limited) discloses tricyclic compounds of formula:
wherein R1 is hydrogen, amino, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxyalkyl or C1—4 fluoroalkyl;
R2 is hydrogen, C1-4 alkyl, C3-4 alkenyl, C3-4 alkynyl, C2-4 hydroxyalkyl C2-4 halogenoalkyl or C1-4 cyanoalkyl;
Ar is phenylene, thiophenediyl, thiazolediyl, pyridinediyl or pyrimidinediyl which may optionally bear one or two substituents selected from halogeno, hydroxy, amino, nitro, cyano, trifluoromethyl, C1-4 alkyl and C1-4 alkoxy; and
R3 is a group of one of the following formulae:—NHCH(CO2H)-A1-Y1—NH-A3-Y3 
or R3 is a N-linked naturally-occurring amino acid selected from the group consisting of L-alanine, L-leucine, L-isoleucine, L-valine and L-phenylalanine. Among the compounds disclosed is the L-Glu-γ-D-Glu compound CB300638, also mentioned in Clinical Cancer Research, 5, November 1999 (Supplement) at #566 (Theti et al.) and Proceedings of the American Association for Cancer Research, 41, March 2000 at #33 (Jackman et al.), as well as in J. Med. Chem., 2000, 43, 1910-1926, where it is disclosed on page 1923 as compound 7b.
WO 95/30673 A1 (British Technology Group Limited) discloses cyclopenta[g]quinazolines of formula:
wherein R1 is hydrogen, amino, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxyalkyl or C1—4 fluoroalkyl;
R2 is hydrogen, C1-4 alkyl, C3-4 alkenyl, C3-4 alkynyl, C2-4 hydroxyalkyl, C2-4 halogenoalkyl or C1-4 cyanoalkyl;
Ar1 is phenylene, thiophenediyl, thiazolediyl, pyridinediyl or pyrimidinediyl which may optionally bear one or two substituents selected from halogeno, hydroxy, amino, nitro, cyano, trifluoromethyl, C1-4 alkyl and C1-4 alkoxy; and
R3 is a group of one of the following formulae:-A1-Ar2-A2-Y1-A5-CON(R)CH(Y4)Y5-A8-X—Ar4 
The α-isoform of the folate receptor (α-FR; membrane-associated folate-binding protein) is a glycosylphosphatidylinositol anchored cell membrane protein that has very high affinity for folic acid and the more biologically relevant reduced—folates (Kd˜0.1 nM). The mechanism of folate internalization is receptor-mediated endocytosis. The α-FR is overexpressed in many carcinomas, particularly those of ovarian origin where it is overexpressed highly and homogeneously in 90% of cases; see Cancer Res. 51, 5329-5338, 1991 (Campbell et al., 1991). Furthermore, high α-FR expression has been linked to aggressive, platinum resistant disease and poor prognosis—see Int. J. Cancer 74, 193-198, 1997 and Int. J. Cancer 79, 121-126, 1998 (both Toffoli et al.). The β-isoform is widely expressed in tumours of epithelial and non-epithelial origin with expression levels being generally low/moderate and high, respectively, reviewed in Critical Rev. Therap. in Drug Carrier Systems 15, 587-627, 1998 (Reddy and Low).
Folate receptors (α and β) are expressed in some adult normal tissues (low to moderate expression). Certain compounds within the general class of cyclopenta[g]quinazolines have been reported to have a high level of selectivity for α-folate receptor expressing human tumour cell lines versus the affinity for the RFC (reduced-folate carrier), Such compounds are disclosed in WO 03/020300 A1, WO 03/020706 A1 and WO 03/020748 A1 (BTG International Limited). Among the compounds disclosed is the L-Glu-γ-D-Glu compound CB300945, also mentioned in Tetrahedron, 63 (7), 12 Feb. 2007, 1537-1543 (Bavetsias et al.) and Cancer Research 65, 15 Dec. 2005, 11721-11728 (Gibbs et al.).
FR-β is normally found in placenta tissues and in hematopoietic cells, where it is expressed in the myelomonocytic lineage and is particularly elevated during neutrophil maturation or during monocyte or macrophage activation. However, the FR-β expressed on normal hematopoietic cells, unlike that on activated macrophages for example, is nonfunctional in that it cannot bind and internalize folate. FR-β is expressed on malignant cells from patients with chronic myelogenous leukaemia (CML), and on malignant cells from approximately 70% of patients with AML.
WO 03/072091-A1 (The Ohio State University Research Foundation) uses the discovery that expression of FR-β is increased in malignant cells from myeloid leukaemia patients by FR-β inducers. The FR-β expressed in myeloid leukaemia cells, preferably AML cells, is functional in that it binds and internalizes folate, unlike the FR-β expressed in the majority of normal hematopoietic cells which is non-functional. Such functional FR-β is a target for folate-conjugated therapeutics.
Jansen, in an abstract from the 13th International Symposium on Chemistry & Biology of Pteridines & Folates entitled “Antifolates in chronic inflammatory diseases/rheumatoid arthritis: what can we learn from cancer and vice versa,” Pteridines, 16: 46, 2005, indicates that methotrexate (MTX) is the anchor drug in treatment regimens for patients with rheumatoid arthritis. He furthermore speculates that cyclopenta[g]quinazoline-based TS inhibitors exhibited binding affinities close to folic acid and could thus be interesting FR-targeted drugs in the treatment of cancer as well as inflammatory diseases.